Clonidine and gaba compounds in a biodegradable polymer carrier

ABSTRACT

Effective treatments of pain for extended periods of time are provided. Through the administration of an effective amount of clonidine and a gamma-aminobutyric acid compound at or near a target site, one can relieve pain caused by diverse sources, including but not limited to spinal disc herniation (i.e. sciatica), spondilothesis, stenosis, discogenic back pain and joint pain, as well as pain that is incidental to surgery. When appropriate formulations are provided within biodegradable polymers, this relief can be continued for at least three days. In some embodiments, the relief can be for at least twenty-five days, at least fifty days, at least one hundred days, at least one hundred and thirty-five days or at least one hundred and eighty days.

This application claims the benefit of the filing date of U.S.Provisional Patent Application Ser. No. 61/419,471, filed on Dec. 3,2010. This entire disclosure is hereby incorporated by reference intothe present disclosure.

BACKGROUND

Pain is typically experienced when the free nerve endings of painreceptors are subject to mechanical, thermal, chemical or other noxiousstimuli. These pain receptors can transmit signals along afferentneurons to the central nervous system and then to the brain. When aperson feels pain, any one or more of a number of problems can beassociated with this sensation, including but not limited to reducedfunction, reduced mobility, complication of sleep patterns, anddecreased quality of life.

The causes of pain include but are not limited to inflammation, injury,disease, muscle stress, the onset of a neuropathic event or syndrome,and damage that can result from surgery or an adverse physical, chemicalor thermal event or from infection by a biologic agent. When a tissue isdamaged, a host of endogenous pain inducing substances, for example,bradykinin and histamine can be released from the injured tissue. Thepain inducing substances can bind to receptors on the sensory nerveterminals and thereby initiate afferent pain signals. After activationof the primary sensory afferent neurons, the projection neurons may beactivated. These neurons carry the signal via the spinothalamic tract tohigher parts of the central nervous system.

One known class of pharmaceuticals to treat pain is opioids. This classof compounds is well-recognized as being among the most effective typeof drugs for controlling pain, such as post-operative pain.Unfortunately, because opioids are administered systemically, theassociated side effects raise significant concerns, including disablingthe patient, depressing the respiratory system, constipation, andpsychoactive effects such as sedation and euphoria, thereby institutinga hurdle to recovery and regained mobility. Consequently, physicianstypically limit the administration of opioids to within the firsttwenty-four hours post-surgery. Thus, it would be preferable to usenon-narcotic drugs that deliver direct, localized pain control at asurgical site.

One pharmaceutical that is known to the medical profession is clonidine,which is widely recognized as an antihypertensive agent that acts as anagonist on the alpha-2-adrenergic receptor and as a neural receptoragonist. In general, clonidine, also referred to as2,6-dichloro-N-2-imidazolidinyldenebenzenamine (C₉H₉Cl₂N₃) may berepresented by the following chemical structure:

Another pharmaceutical that is known to the medical profession is thegamma-aminobutyric acid (GABA) compound gabapentin, which is approved inthe United States for use in treating epilepsy and post-herpeticneuralgia, in immediate-release tablets and capsules. Pharmaceuticalsthat can increase the available amount of GABA are also available.

However, to date clonidine and GABA compounds have not been widelyappreciated as a localized and effective treatment for pain. Thus, thereis a need to develop effective devices and compositions containingclonidine and a GABA compound for this application.

SUMMARY

Compositions and methods are provided comprising clonidine or itspharmaceutically acceptable salts and a GABA compound that areadministered in order to treat pain and/or inflammation. Thecompositions and methods may for example be used to treat pain due to aspinal disc herniation (i.e., sciatica), spondilothesis, stenosis,osteoarthritis, carpal/tarsal tunnel syndrome, tendonitis,temporomandibular joint disorder (TMJ), discogenic back pain, joint painor inflammation.

According to one embodiment, there is an implantable device comprising:clonidine, wherein the clonidine comprises from about 0.1 wt. % to about30 wt. % of the formulation and a GABA compound, and at least onebiodegradable polymer.

In some embodiments, the drug depot comprises clonidine and a GABAcompound that is in the drug depot in an amount of from about 0.1% toabout 75% by weight.

In some embodiments, when the drug depot comprises a GABA compound inthe drug depot, the GABA compound is in the drug depot in an amount offrom about 0.1% to about 75% by weight.

The implantable device may for example, be part of a drug depot. Thedrug depot may: (i) consist of only the clonidine (or one or more of itspharmaceutically acceptable salts) and a GABA compound and thebiodegradable polymer(s); or (ii) consist essentially of the clonidine(and/or one or more of its pharmaceutically acceptable salts) and a GABAcompound and the biodegradable polymer(s); or (iii) comprise theclonidine (and/or one or more of its pharmaceutically acceptable salts),and a GABA compound and the biodegradable polymer(s) and one or moreother active ingredients, surfactants, excipients or other ingredientsor combinations thereof. When there are other active ingredients,surfactants, excipients or other ingredients or combinations thereof inthe formulation, in some embodiments these other compounds orcombinations thereof comprise less than 50 wt. %. less than 40 wt. %,less than 30 wt. %, less than 20 wt. %, less than 19 wt. %, less than 18wt. %, less than 17 wt. %, less than 16 wt. %, less than 15 wt. %, lessthan 14 wt. %, less than 13 wt. %, less than 12 wt. %, less than 11 wt.%, less than 10 wt. %, less than 9 wt. %, less than 8 wt. %, less than 7wt. %, less than 6 wt. %, less than 5 wt. %, less than 4 wt. %, lessthan 3 wt. %, less than 2 wt. %, less than 1 wt. % or less than 0.5 wt.%.

According to another embodiment, there is an implantable device forreducing, preventing or treating pain in a patient in need of suchtreatment, the implantable device comprising clonidine and agamma-aminobutyric acid (GABA) compound in an amount from about 0.1 wt.% to about 99 wt. % of the implantable device, and at least onebiodegradable polymer, wherein the implantable device is capable ofreleasing clonidine and the GABA compound over a period of at leastthree days.

According to another embodiment, there is an implantable drug depot forreducing, preventing or treating pain in a patient in need of suchtreatment, the implantable drug depot comprising clonidine hydrochloridein an amount of from about 0.1 wt. % to about 30 wt. % of the drug depotand baclofen, vigabatrin, gabapentin, pregabalin, gamma-amino-phosphinicacid, or1-{[(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid and at least one polymer, wherein the at least one polymercomprises one or more of poly(lactide-co-glycolide) (PLGA), polylactide(PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone or a combination thereof.

According to yet another embodiment, there is a method for treatingacute pain, wherein said method comprises implanting a drug depot in anorganism to reduce, prevent or treat pain, wherein said drug depotcomprises clonidine in an amount from about 0.1 wt. % to about 30 wt. %of the drug depot and baclofen, vigabatrin, gabapentin, pregabalin,gamma-amino-phosphinic-acid or 1-{[(alphaisobutanoyloxyethoxy)-carbonyl]aminomethyl}-1-cyclohexane acetic acid,and at least one biodegradable polymer.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a number of common locations within a patient thatmay be sites at which pain occurs and locations at which a drug depotcontaining clonidine can locally be administered thereto.

FIG. 2 illustrates a schematic dorsal view of the spine and sites atwhich a drug depot containing clonidine can locally be administeredthereto.

FIG. 3 is a bar graph illustration showing that Von Frey withdrawalthreshold is increased by gabapentin in rats with an injury to thesciatic nerve.

FIG. 4 is a bar graph illustration showing that thermal withdrawallatency is increased by gabapentin in rats with an injury to the sciaticnerve.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

DEFINITIONS

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

A “drug depot” is the composition in which the clonidine and GABAcompound is administered to the body. Thus, a drug depot may comprise aphysical structure to facilitate implantation and retention in a desiredsite (e.g., a disc space, a spinal canal, a tissue of the patient,particularly at or near a site of chronic pain, etc.). The drug depotmay also comprise the drug itself. The term “drug” as used herein isgenerally meant to refer to any substance that alters the physiology ofa patient. The term “drug” may be used interchangeably herein with theterms “therapeutic agent,” “therapeutically effective amount,” and“active pharmaceutical ingredient” or “API.” It will be understood thatunless otherwise specified a “drug” formulation may include more thanone therapeutic agent, wherein exemplary combinations of therapeuticagents include a combination of two or more drugs. The drug provides aconcentration gradient of the therapeutic agent for delivery to thesite. In various embodiments, the drug depot provides an optimal drugconcentration gradient of the therapeutic agent at a distance of up toabout 0.01 cm to about 20 cm from the administration site and comprisesclonidine and a GABA compound. A drug depot may also include a pump orpellet.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain or spasticity, improvement in the condition throughmuscle relaxation, etc. The dosage administered to a patient can be assingle or multiple doses depending upon a variety of factors, includingthe drug's administered pharmacokinetic properties, the route ofadministration, patient conditions and characteristics (sex, age, bodyweight, health, size, etc.), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired. In some embodiments theformulation is designed for immediate release. In other embodiments theformulation is designed for sustained release. In other embodiments, theformulation comprises one or more immediate release surfaces and one ormore sustained release surfaces.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, etc.) can break down or degrade within thebody to non-toxic components after or while a therapeutic agent has beenor is being released. By “bioerodible” it is meant that the depot willerode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction. By “bioabsorbable” it is meant that the depot will be brokendown and absorbed within the human body, for example, by a cell ortissue. “Biocompatible” means that the depot will not cause substantialtissue irritation or necrosis at the target tissue site.

In some embodiments, the drug depot has pores that allow release of thedrug from the depot. The drug depot will allow fluid in the depot todisplace the drug. However, cell infiltration into the depot will beprevented by the size of the pores of the depot. In this way, in someembodiments, the depot should not function as a tissue scaffold andallow tissue growth. Rather, the drug depot will solely be utilized fordrug delivery. In some embodiments, the pores in the drug depot will beless than 250 to 500 microns. This pore size will prevent cells frominfiltrating the drug depot and laying down scaffolding cells. Thus, inthis embodiment, drug will elute from the drug depot as fluid enters thedrug depot, but cells will be prevented from entering. In someembodiments, where there are little or no pores, the drug will elute outfrom the drug depot by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body.

The phrases “sustained release” and “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually releases a streamof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release stream is intended to encompass releasethat occurs as the result of biodegradation in vivo of the drug depot,or a matrix or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s).

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The two types of formulations (sustain release and immediate release)may be used in conjunction. The sustained release and immediate releasemay be in one or more of the same depots. In various embodiments, thesustained release and immediate release may be part of separate depots.For example a bolus or immediate release formulation of clonidine may beplaced at or near the target site and a sustain release formulation mayalso be placed at or near the same site. Thus, even after the bolusbecomes completely accessible, the sustain release formulation wouldcontinue to provide the active ingredient for the intended tissue.

In various embodiments, the drug depot can be designed to cause aninitial burst dose of therapeutic agent within the first twenty-four toseventy-two hours after implantation. “Initial burst” or “burst effect”or “bolus dose” refers to the release of therapeutic agent from thedepot during the first twenty-four hours to seventy-two hours after thedepot comes in contact with an aqueous fluid (e.g., synovial fluid,cerebral spinal fluid, etc.). The “burst effect” is believed to be dueto the increased release of therapeutic agent from the depot. Inalternative embodiments, the depot (e.g., gel) is designed to avoid orreduce this initial burst effect (e.g., by applying an outer polymercoating to the depot).

“Treating” or “treatment” of a disease or condition refers to executinga protocol that may include administering one or more drugs to a patient(human, other normal or otherwise or other mammal), in an effort toalleviate signs or symptoms of the disease or condition. Alleviation canoccur prior to signs or symptoms of the disease or condition appearing,as well as after their appearance. Thus, treating or treatment includespreventing or prevention of disease or undesirable condition. Inaddition, treating or treatment does not require complete alleviation ofsigns or symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient. “Reducingpain and/or inflammation” includes a decrease in pain and/orinflammation and does not require complete alleviation of pain and/orinflammation signs or symptoms, and does not require a cure. In variousembodiments, reducing pain and/or inflammation includes even a marginaldecrease in pain and/or inflammation. By way of example, theadministration of the effective dosage of clonidine may be used toprevent, treat or relieve the symptoms of pain and/or inflammation fordifferent diseases or conditions. These disease/conditions may compriseoral-facial diseases, bursitis, tendonitis, chronic inflammatorydiseases, including, but not limited to autoimmune diseases, such asmultiple sclerosis, rheumatoid arthritis, osteoarthritis, insulindependent diabetes (type I diabetes), systemic lupus erythrematosis andpsoriasis, immune pathologies induced by infectious agents, such ashelminthic (e.g., leishmaniasis) and certain viral infections, includingHIV, and bacterial infections, including Lyme disease, tuberculosis andlepromatous leprosy, tissue transplant rejection, graft versus hostdisease and atopic conditions, such as asthma and allergy, includingallergic rhinitis, gastrointestinal allergies, including food allergies,eosinophilia, conjunctivitis or glomerular nephritis. In someembodiments, the drug depot containing the therapeutic agent is notadministered in, to or near the eye.

One chronic condition is sciatica. In general, sciatica is an example ofpain that can transition from acute to neuropathic pain. Sciatica refersto pain associated with the sciatic nerve which runs from the lower partof the spinal cord (the lumbar region), down the back of the leg and tothe foot. Sciatica generally begins with a herniated disc. The herniateddisc itself leads to local immune system activation. The herniated discalso may damage the nerve root by pinching or compressing it, leading toadditional immune system activation in the area. In various embodiments,the clonidine may be used to reduce, treat, or prevent sciatic painand/or inflammation by locally administering the clonidine at one ormore target tissue sites (e.g., nerve root, dorsal root ganglion, focalsites of pain, at or near the spinal column, etc.).

In some embodiments, the drug depot can be used to treat one or moretarget tissue sites that are involved in conditions/diseases, such asfor example, rheumatoid arthritis, osteoarthritis, sciatica, carpaltunnel syndrome, lower back pain, lower extremity pain, upper extremitypain, cancer, tissue pain and pain associated with injury or repair ofcervical, thoracic, and/or lumbar vertebrae or intervertebral discs,rotator cuff, articular joint, TMJ, tendons, ligaments, muscles, asurgical wound site or an incision site or the like.

In some embodiments, the clonidine and GABA compound drug depot can beused to treat glaucoma. Glaucoma is an eye condition in whichintraocular pressure (IOP) is increased to an abnormal level. Thisincrease in IOP is often due to increase in vitreous fluid pressure inthe eye. The increase in intraocular pressure causes an opticalneuropathy to develop, namely death of certain cells in the retina,leading to restriction in the field of view and eventual blindness ifleft untreated.

In some embodiments, the drug depot can be implanted in, at or near theeye or eye tissue so that the depot allows contact with the vitreousfluid or aqueous humor of the eye and release of the drug (e.g.,clonidine and GABA compound) from the depot over time to treat glaucoma.Examples of eye tissue for implantation of the drug depot include, forexample, anterior chamber of the eye, sclera, wall of the sclera,cornea, Schlemm's canal, trabecular meshwork or other tissue within theeye. In some embodiments, the drug depot can be implanted under theeyelid to allow release of the clonidine and GABA compound to treatglaucoma by reducing or stabilizing IOP. The release of drug from thedrug depot can be over one or more months.

The term “implantable” as utilized herein refers to a biocompatibledevice (e.g., drug depot) retaining potential for successful placementwithin a mammal. The expression “implantable device” and expressions ofthe like import as utilized herein refers to an object implantablethrough surgery, injection, or other suitable means whose primaryfunction is achieved either through its physical presence or mechanicalproperties.

“Localized” delivery includes delivery where one or more drugs aredeposited within a tissue, for example, a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 0.1cm, or preferably within about 10 cm, for example) thereto. For example,the drug dose delivered locally from the drug depot may be, for example,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9% lessthan the oral dosage or injectable dose. In turn, systemic side effects,such as for example, liver transaminase elevations, hepatitis, liverfailure, myopathy, constipation, etc. may be reduced or eliminated.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

The phrase “pain management medication” includes one or more therapeuticagents that are administered to prevent, alleviate or remove painentirely. These include anti-inflammatory agents, muscle relaxants,analgesics, anesthetics, narcotics, and so forth, and combinationsthereof.

The phrase “release rate profile” refers to the percentage of activeingredient that is released over fixed units of time, e.g., mcg/hr,mcg/day, 10% per day for ten days, etc. As persons of ordinary skillknow, a release rate profile may, but need not, be linear. By way of anon-limiting example, the drug depot may be a ribbon-like fiber thatreleases the clonidine over a period of time (see FIGS. 5-34).

The term “solid” is intended to mean a rigid material, while,“semi-solid” is intended to mean a material that has some degree offlexibility, thereby allowing the depot to bend and conform to thesurrounding tissue requirements.

“Targeted delivery system” provides delivery of one or more drugsdepots, gels or depots dispersed in the gel having a quantity oftherapeutic agent that can be deposited at or near the target site asneeded for treatment of pain, inflammation or other disease orcondition.

The abbreviation “DLG” refers to poly(DL-lactide-co-glycolide).

The abbreviation “DL” refers to poly(DL-lactide).

The abbreviation “LG” refers to poly(L-lactide-co-glycolide).

The abbreviation “CL” refers to polycaprolactone.

The abbreviation “DLCL” refers to poly(DL-lactide-co-caprolactone).

The abbreviation “LCL” refers to poly(L-lactide-co-caprolactone).

The abbreviation “G” refers to polyglycolide.

The abbreviation “PEG” refers to poly(ethylene glycol).

The abbreviation “PLGA” refers to poly(lactide-co-glycolide) also knownas poly(lactic-co-glycolic acid), which are used interchangeably.

The abbreviation “PLA” refers to polylactide.

The abbreviation “POE” refers to poly(orthoester).

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

Clonidine and GABA Compounds

When referring to clonidine or GABA compound, unless otherwise specifiedor apparent from context it is understood that the inventors are alsoreferring to pharmaceutically acceptable salts. One well-knowncommercially available salt for clonidine is its hydrochloride salt.Some other examples of potentially pharmaceutically acceptable saltsinclude those salt-forming acids and bases that do not substantiallyincrease the toxicity of a compound, such as, salts of alkali metalssuch as magnesium, potassium and ammonium, salts of mineral acids suchas hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acids, as well as salts of organic acids such as tartaric,acetic, citric, malic, benzoic, glycollic, gluconic, gulonic, succinic,arylsulfonic, e.g., p-toluenesulfonic acids, and the like.

Further, when referring to clonidine and GABA compound the activeingredient may not only be in the salt form, but also in the base form(e.g., free base). In various embodiments, if it is in the base form, itmay be combined with polymers under conditions in which there is notsevere polymer degradation, as may be seen upon heat or solventprocessing that may occur with PLGA or PLA. By way of a non limitingexample, when formulating clonidine with poly(orthoesters) it may bedesirable to use the clonidine base formulation. By contrast, whenformulating clonidine with PLGA, it may be desirable to use the HCl saltform. In some embodiments, the clonidine may be incorporated into apolymer core with a polymer and then coated with the same or differentpolymer.

Pharmaceutically acceptable salts of clonidine or GABA compound includesalts prepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic or organic bases, inorganic or organic acids andfatty acids. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethyl amine, tripropylamine,tromethamine, and the like. When the compound of the current applicationis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic,phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonicacid, trifluoroacetic acid, and the like. Fatty acid salts may also beused, eg., fatty acid salts having greater than 2 carbons, greater than8 carbons or greater than 16 carbons, such as butyric, caprioc,caprylic, capric, lauric, mystiric, palmitic, stearic, arachidic or thelike.

In some embodiments, in order to reduce the solubility of the clonidineto assist in obtaining a controlled release depot effect, clonidine isutilized as the free base or utilized in a salt which has relativelylower solubility. For example, the present application can utilize aninsoluble salt such as a fatty acid salt. Representative fatty acidsalts include salts of oleic acid or linoleic acid. In preferredembodiments fatty acid salts with between 8 to 20 carbons are used toproduce salts with low solubility, such as clonidine palmeate andclonidine stearate. Most preferably, fatty acid salts with between 12 to18 carbons are used. Other embodiments can utilize a lipid soluble saltof clonidine.

Suitable clonidine depots for use in the present application aredescribed in U.S. Ser. No. 12/420,197, filed Apr. 8, 2009 and publishedas US20090264490. The entire disclosure is herein incorporated byreference.

The GABA compounds used in the treatment methods and in the deviceinclude compounds of gamma-aminobutyric acid. Such compounds includegabapentin (241-(aminomethyl)cyclohexyl]acetic acid), pregabalin((S)-3-(aminomethyl)-5-methylhexanoic acid), vigabatrin(4-aminohex-5-enoic acid), and baclofen(4-amino-3-(4-chlorophenyl)butanoic acid), which are 3′-alkylated GABAcompounds. Additional GABA compounds that may be used are described inSatzinger et al., U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat.No. 5,563,175; Horwell et al., U.S. Pat. No. 6,020,370; Silverman etal., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932;Silverman et al., U.S. Pat. No. 6,117,906; WO 02/00209); Silverman etal., PCT Publication No. WO 92/09560; Silverman et al., PCT PublicationNo. WO 93/23383; Horwell et al., PCT Publication No. WO 97/29101,Horwell et al., PCT Publication No. WO 97/33858; Horwell et al., PCTPublication No. WO 97/33859; Bryans et al., PCT Publication No. WO98/17627; Guglietta et al., PCT Publication No. WO 99/08671; Bryans etal., PCT Publication No. WO 99/21824; Bryans et al., PCT Publication No.WO 99/31057; WO 98/23383; Bryans et al., J. Med. Chem. 1998, 41,1838-1845; Bryans et al., Med. Res. Rev. 1999, 19, 149-177, US Gugliettaet al., WO 99/08670; Bryans et al., WO 99/21824; US Bryans et al., UK GB2 374 595), Belliotti et al., PCT Publication No. WO 99/31074; Bryans etal., PCT Publication No. WO 99/31075; Bryans et al., PCT Publication No.WO 99/61424; Bryans et al., PCT Publication No. WO 00/15611; Bryans, PCTPublication No. WO 00/31020; Bryans et al., PCT Publication No. WO00/50027; and Bryans et al., PCT Publication No. WO 02/00209). Newclasses of GABA compounds, which are bicyclic amino acid derivatives,have been recently described by Bryans et al., PCT Publication No. WO01/28978; Blakemore et al., PCT Pub. No. WO 02/085839; Blakemore et al.,U.S. Pat. No. 5,596,900; and Blakemore et al., PCT Pub. No. WO02/090318. These disclosures are herein incorporated by reference intothe present disclosure.

In one embodiment, the GABA compound comprises1-{[(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid, baclofen, vigabatrin, gabapentin, pregabalin,gamma-amino-phosphinic acid or1-{[(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid, fengabine, GBL (gamma-Butyrolactone), GHB(gamma-Hydroxybutyric acid, 4-hydroxybutanoic acid or sodium oxybate),picamilon and progabide, (s)-(+)-4-amino-3-(2-methylpropyl) butanoicacid

In another embodiment, GABA compounds include pharmaceuticals that canincrease locally the available amount of endogenous GABA or GABA analogsfollowing their local or systemic administration. These includepharmaceuticals that interfere with GABA or GABA analog reuptake such astiagabine, stiripentol, deramciclane, hyperforin or a combinationthereof. GABA compounds also include pharmaceuticals that interfere withthe degradation of GABA or GABA analogs such as phenelzine, gabaculine,valproate, vigabatrin, lemon balm or a combination thereof.

In some embodiments, the GABA compound is released locally from thedevice at a dose of from about 0.3 mg/day or about 1.8 mg/day or about3.6 mg/day to about 180 mg/day or about 360 mg/day. In some embodiments,the GABA compound is released from the device at a dose of 0.75 mg to 16mg per day. In some embodiments, the initial burst or bolus release isabout 2 to 20 times higher from 1 hour to about two weeks than thesustained release daily dose released from the device.

In some embodiments, the GABA compound comprises gabapentin, which isreleased from the device at a dosage of from about 0.3 mg or 1 mg toabout 8 mg, 10 mg, 16 mg or 32 mg per day. In some embodiments, the GABAcompound comprises pregabalin, which is released from the device at adosage of from about 0.1 mg or 0.3 mg to about 1 mg, 3 mg, 5 mg or 10 mgper day. In some embodiments, the clonidine can be released from thedepot at a dose of 0.002 mg to 16 mg per day.

In some embodiments, the ratio of gabapentin to clonidine would be300:1. For pregabalin, the ratio would be approximately 100:1. In someembodiments, the drug depot releases 300 mg of pregabalin per day.

The GABA compound compliments the anti-inflammatory and analgesic effectof clonidine in the depot.

In some embodiments, the drug depot comprises clonidine and a GABAcompound that is in the drug depot in an amount of from about 0.1% toabout 75% by weight.

In some embodiments, when the drug depot comprises a GABA compound inthe drug depot, the GABA compound is in the drug depot in an amount offrom about 0.1% to about 75% by weight.

In some embodiments, the drug depot comprises both a GABA compound andclonidine in a single formulation. In some embodiments, the GABAcompound can be in a separate depot from the clonidine.

In some embodiments, a GABA compound, a steroid, bupivacaine, lidocaineand/or clonidine can be administered in an immediate release orsustained release liquid by injection before, after, or during theadministration of the clonidine depot.

The clonidine and GABA compound or its pharmaceutically acceptable saltmay be administered with a muscle relaxant. Exemplary muscle relaxantsinclude by way of example and not limitation, alcuronium chloride,atracurium bescylate, carbamate, carbolonium, carisoprodol,chlorphenesin, chlorzoxazone, cyclobenzaprine, dantrolene, decamethoniumbromide, fazadinium, gallamine triethiodide, hexafluorenium,meladrazine, mephensin, metaxalone, methocarbamol, metocurine iodide,pancuronium, pridinol mesylate, styramate, suxamethonium, suxethonium,thiocolchicoside, tizanidine, tolperisone, tubocuarine, vecuronium, orcombinations thereof.

The drug depot may comprise other therapeutic agents in addition to theclonidine and GABA compound as well. These therapeutic agents, invarious embodiments, block the transcription or translation of TNF-α orother proteins in the inflammation cascade. Suitable therapeutic agentsinclude, but are not limited to, integrin antagonists, alpha-4 beta-7integrin antagonists, cell adhesion inhibitors, interferon gammaantagonists, CTLA4-Ig agonists/antagonists (BMS-188667), CD40 ligandantagonists, Humanized anti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1mAb (Critical Therapeutics Inc.), anti-IL2R antibodies (daclizumab,basilicimab), ABX (anti IL-8 antibodies), recombinant human IL-10, orHuMax IL-15 (anti-IL 15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors, such Kineret®(anakinra) which is a recombinant, non-glycosylated form of the humaninerleukin-1 receptor antagonist (IL-1Ra), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors, and/or kainate receptors. Interleukin-1 receptor antagonists,thalidomide (a TNF-α release inhibitor), thalidomide analogs (whichreduce TNF-α production by macrophages), bone morphogenetic protein(BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator),quinapril (an inhibitor of angiotensin II, which upregulates TNF-α),interferons such as IL-11 (which modulate TNF-α receptor expression),and aurin-tricarboxylic acid (which inhibits TNF-α), may also be usefulas therapeutic agents for reducing inflammation. It is furthercontemplated that where desirable a pegylated form of the above may beused. Examples of still other therapeutic agents include NF kappa Binhibitors such as glucocorticoids, antioxidants, such asdithiocarbamate, and other compounds, such as, for example,sulfasalazine.

Examples of therapeutic agents suitable for use also include, but arenot limited to an anti-inflammatory agent, an analgesic agent, or anosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, apazone, celecoxib, diclofenac,diflunisal, enolic acids (piroxicam, meloxicam), etodolac, fenamates(mefenamic acid, meclofenamic acid), gold, ibuprofen, indomethacin,ketoprofen, ketorolac, nabumetone, naproxen, nimesulide, salicylates,sulfasalazine[2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid, sulindac, tepoxalin or tolmetin; as well as antioxidants, such asdithiocarbamate, steroids, such as fluocinolone, cortisol, cortisone,hydrocortisone, fludrocortisone, prednisone, prednisolone,methylprednisolone, triamcinolone, betamethasone, dexamethasone,beclomethasone, fluticasone or a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include, butare not limited to, a bone morphogenetic protein, a growthdifferentiation factor (e.g., GDF-5), a LIM mineralization protein, CDMPor progenitor cells or a combination thereof.

Suitable analgesic agents include, but are not limited to,acetaminophen, bupivacaine, lidocaine, opioid analgesics such asbuprenorphine, butorphanol, dextromoramide, dezocine,dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil,hydrocodone, hydromorphone, ketobemidone, levomethadyl, mepiridine,methadone, morphine, nalbuphine, opium, oxycodone, papavereturn,pentazocine, pethidine, phenoperidine, piritramide, dextropropoxyphene,remifentanil, tilidine, tramadol, codeine, dihydrocodeine, meptazinol,dezocine, eptazocine, flupirtine, amitriptyline, carbamazepine,gabapentin, pregabalin, or a combination thereof.

The therapeutic agent in the device may include, but is not limited to,members of the fibroblast growth factor family, including acidic andbasic fibroblast growth factor (FGF-1 and FGF-2) and FGF-4, members ofthe platelet-derived growth factor (PDGF) family, including PDGF-AB,PDGF-BB and PDGF-AA; EGFs; the TGF-β superfamily, including TGF-131, 2or 3; osteoid-inducing factor (OIF); angiogenin(s); endothelins;hepatocyte growth factor or keratinocyte growth factor; members of thebone morphogenetic proteins (BMP's) BMP-1, BMP-3, BMP-2; OP-1, BMP-2A,BMP-2B, or BMP-7; HBGF-1 or HBGF-2; growth differentiation factors(GDF's); members of the hedgehog family of proteins, including indian,sonic and desert hedgehog; ADMP-1; other members of the interleukin (IL)family; or members of the colony-stimulating factor (CSF) family,including CSF-1, G-CSF, and GM-CSF, or isoforms thereof; or VEGF, NELL-1(neural epidermal growth factor-like 1), CD-RAP (cartilage-derivedretinoic acid-sensitive protein) or combinations thereof.

In some embodiments, the device comprises osteogenic proteins. Exemplaryosteogenic proteins include, but are not limited to, OP-1, OP-2, OP-3,BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11,BMP-12, BMP-13, BMP-14, BMP-15, GDF-1, GDF-2, GDF-3, GDF-5, GDF-6,GDF-7, GDF-8, GDF-9, GDF-10, GDF-11, GDF-12, CDMP-1, CDMP-2, CDMP-3,DPP, Vg-1, Vgr-1, 60A protein, NODAL, UNIVIN, SCREW, ADMP, NEURAL, andTGF-beta. As used herein, the terms “morphogen,” “bone morphogen,”“BMP,” “osteogenic protein” and “osteogenic factor” embrace the class ofproteins typified by human osteogenic protein 1 (hOP-1).

Exemplary growth factors include, but are not limited to, members of thetransforming growth factor beta family, including bone morphogeneticprotein 2 (BMP-2); bone morphogenetic protein 4 (BMP-4); andtransforming growth factors beta-1, beta-2, and beta-3 (potentkeratinocyte growth factors). Other useful members of the transforminggrowth factor beta family include BMP-3, BMP-5, BMP-6, BMP-9, DPP, Vg1,Vgr, 60A protein, GDF-1, GDF-3, GDF-5, GDF-6, GDF-7, CDMP-1, CDMP-2,CDMP-3, BMP-10, BMP-11, BMP-13, BMP-15, Univin, Nodal, Screw, ADMP,Neural, and amino acid sequence variants thereof. Other growth factorsinclude epidermal growth factor (EGF), which induces proliferation ofboth mesodermal and ectodermal cells, particularly keratinocytes andfibroblasts; platelet-derived growth factor (PDGF), which exertsproliferative effects on mesenchymal cells; fibroblast growth factor(FGF), both acidic and basic; and insulin-like growth factor 1 (IGF-1)or 2 (IGF-2), which mediate the response to growth hormone, particularlyin bone growth. Further growth factors include osteogenic proteins. Aparticularly preferred osteogenic protein is OP-1, also known as bonemorphogenetic protein 7 (BMP-7). OP-1 is a member of the transforminggrowth factor beta gene superfamily.

The clonidine and GABA compound may also be administered with non-activeingredients. These non-active ingredients may have multi-functionalpurposes including the carrying, stabilizing and controlling the releaseof the therapeutic agent(s). The sustained release process, for example,may be by a solution-diffusion mechanism or it may be governed by anerosion-sustained process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material that can bebiodegradable.

Exemplary excipients that may be formulated with clonidine and GABAcompound in addition to the biodegradable polymer include but are notlimited to MgO (e.g., 1 wt. %), 5050 DLG 6E (Surmodics Pharmaceuticals,Birmingham, Ala.), 5050 DLG 1A (Surmodics Pharmaceuticals, Birmingham,Ala.), mPEG, propylene glycol, mannitol, TBO-Ac, mPEG, Span-65, Span-85,pluronic F127, TBO-Ac, sorbitol, cyclodextrin, maltodextrin, pluronicF68, CaCl, 5050 DLG-7A (Surmodics Pharmaceuticals, Birmingham, Ala.) andcombinations thereof. In some embodiments, the excipients comprise fromabout 0.001 wt. % to about 50 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 40wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 30 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 20wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 10 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 50wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 2 wt. % of the formulation.

In various embodiments, the non-active ingredients will be durablewithin the tissue site for a period of time equal to or greater than(for biodegradable components) or greater than (for non-biodegradablecomponents) the planned period of drug delivery.

In some embodiments, the depot material may have a melting point orglass transition temperature close to or higher than body temperature,but lower than the decomposition or degradation temperature of thetherapeutic agent. However, the pre-determined erosion of the depotmaterial can also be used to provide for slow release of the loadedtherapeutic agent(s). Non-biodegradable polymers include but are notlimited to PVC and polyurethane. In some embodiments, a plasticizer isused to lower glass translation temperature in order to affect stabilityof the drug depot.

In some embodiments, the polymer can be in powdered form having aparticle size predominantly in a range from about 3.5 to about 10micrometers that can be reconstituted for delivery.

In various embodiments, the drug depot comprises clonidine, bupivacaineor lidocaine and the GABA and a biodegradable polymer in amorphous,crystalline or semicrystalline form; where the crystalline form mayinclude polymorphs, solvates or hydrates.

In some embodiments, the clonidine can be in powdered form having aparticle sizes predominantly in a range from about 3.5 to about 10micrometers that can be reconstituted for delivery.

In some embodiments, the drug depot has a modulus of elasticity in therange of about 1×10² to about 6×10⁵ dyn/cm², or 2×10⁴ to about 5×10⁵dyn/cm², or 5×10⁴ to about 5×105 dyn/cm². In some embodiments, the drugdepot is in the form of a solid. In some embodiments, the drug depotcomprises clonidine, bupivacaine or lidocaine and the GABA.

In some embodiments, the clonidine, bupivacaine, and/or lidocaine, andthe GABA is administered in a depot that is solid or in semi-solid form.The solid or semi-solid form of the depot may have a pre-dosed viscosityin the range of about 1 to about 2000 centipoise (cps), 1 to about 200cps, or 1 to about 100 cps. After the solid or semi-solid depot isadministered to the target site, the viscosity of the semi-solid orsolid depot will increase and the semi-solid will have a modulus ofelasticity in the range of about 1×−10² to about 6×10⁵ dynes/cm², or2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In various embodiments, the semi-solid or solid depot may comprise apolymer having a molecular weight, as shown by the inherent viscosity,from about 0.10 dL/g to about 1.2 dL/g or from about 0.10 dL/g to about0.40 dL/g. Other IV ranges include but are not limited to about 0.05 toabout 0.15 dL/g, about 0.10 to about 0.20 dL/g, about 0.15 to about 0.25dL/g, about 0.20 to about 0.30 dL/g, about 0.25 to about 0.35 dL/g,about 0.30 to about 0.35 dL/g, about 0.35 to about 0.45 dL/g, about 0.40to about 0.45 dL/g, about 0.45 to about 0.55 dL/g, about 0.50 to about0.70 dL/g, about 0.55 to about 0.6 dL/g, about 0.60 to about 0.80 dL/g,about 0.70 to about 0.90 dL/g, about 0.80 to about 1.00 dL/g, about 0.90to about 1.10 dL/g, about 1.0 to about 1.2 dL/g, about 1.1 to about 1.3dL/g, about 1.2 to about 1.4 dL/g, about 1.3 to about 1.5 dL/g, about1.4 to about 1.6 dL/g, about 1.5 to about 1.7 dL/g, about 1.6 to about1.8 dL/g, about 1.7 to about 1.9 dL/g, or about 1.8 to about 2.1 dL/g.

In some embodiments, the drug depot may not be fully biodegradable. Forexample, the drug depot may comprise polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics, methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO(pluronics) or combinations thereof. Typically, these types of drugdepots may need to be removed after a certain amount of time.

In some instances, it may be desirable to avoid having to remove thedrug depot after use. In those instances, the depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As a function of the chemistry of the biodegradablematerial, the mechanism of the degradation process can be hydrolyticalor enzymatical in nature, or both. In various embodiments, thedegradation can occur either at the surface (heterogeneous or surfaceerosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion).

In various embodiments, the depot may comprise a bioerodible, abioabsorbable, and/or a biodegradable biopolymer that may provideimmediate release, or sustained release of the clonidine. Examples ofsuitable sustained release biopolymers include but are not limited topoly(alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA),polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly(alpha-hydroxy acids), poly(orthoester)s (POE),polyaspirins, polyphosphagenes, collagen, starch, pre-gelatinizedstarch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin,vitamin E compounds, such as alpha tocopheryl acetate, d-alphatocopheryl succinate, D,L-lactide, or L-lactide, -caprolactone,dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,PEGT-PBT copolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA,PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB(sucrose acetate isobutyrate) or combinations thereof. As persons ofordinary skill are aware, mPEG and/or PEG may be used as a plasticizerfor PLGA, but other polymers/excipients may be used to achieve the sameeffect. mPEG imparts malleability to the resulting formulations. In someembodiments, these biopolymers may also be coated on the drug depot toprovide the desired release profile. In some embodiments, the coatingthickness may be thin, for example, from about 5, 10, 15, 20, 25, 30,35, 40, 45 or 50 microns to thicker coatings 60, 65, 70, 75, 80, 85, 90,95, 100 microns to delay release of the drug from the depot. In someembodiments, the range of the coating on the drug depot ranges fromabout 5 microns to about 250 microns or 5 microns to about 200 micronsto delay release from the drug depot.

In various embodiments, the drug depot comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone, L-lactide-co-ε-caprolactoneor a combination thereof. In some embodiments, the drug depot comprisesone or more polymers (e.g., poly-D-lactide, caprolactone, etc.) havingan inherent viscosity of 0.6 to about 1.0 dL/gm and a MW of 50,000 toabout 125,000 Da.

In some embodiments, the drug depot comprises one or more polymers(e.g., PLA, PLGA, etc.) having a MW of from about 15,000 to about150,000 Da or from about 25,000 to about 100,000 Da.

As persons of ordinary skill in the art are aware, an implantable depotcompositions having a blend of polymers with different end groups areused the resulting formulation will have a lower burst index and aregulated duration of delivery. For example, one may use polymers withacid (e.g., carboxylic acid) and ester end groups (e.g., methyl or ethylester end groups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the L/G (lactic acid/glycolic acid) or G/CL(glycolic acid/polycaprolactone) ratio for a given polymer) there willbe a resulting depot composition having a regulated burst index andduration of delivery. For example, a depot composition having a polymerwith a L/G ratio of 50:50 may have a short duration of delivery rangingfrom about two days to about one month; a depot composition having apolymer with a L/G ratio of 65:35 may have a duration of delivery ofabout two months; a depot composition having a polymer with a L/G ratioof 75:25 or L/CL ratio of 75:25 may have a duration of delivery of aboutthree months to about four months; a depot composition having a polymerratio with a L/G ratio of 85:15 may have a duration of delivery of aboutfive months; a depot composition having a polymer with a L/CL ratio of25:75 or PLA may have a duration of delivery greater than or equal tosix months; a depot composition having a terpolymer of CL/G/L with Ggreater than 50% and L greater than 10% may have a duration of deliveryof about one month and a depot composition having a terpolymer of CL/G/Lwith G less than 50% and L less than 10% may have a duration months upto six months. In general, increasing the G content relative to the CLcontent shortens the duration of delivery whereas increasing the CLcontent relative to the G content lengthens the duration of delivery.Thus, among other things, depot compositions having a blend of polymershaving different molecular weights, end groups and comonomer ratios canbe used to create a depot formulation having a lower initial burst and aregulated duration of delivery.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfate,sodium bisulfite, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. If the depot is to be placed inthe spinal area, in various embodiments, the depot may comprise sterilepreservative free material.

The depot can be different sizes, shapes and configurations. There areseveral factors that can be taken into consideration in determining thesize, shape and configuration of the drug depot. For example, both thesize and shape may allow for ease in positioning the drug depot at thetarget tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a cylinder such as a rod or fiber, a flat surfacesuch as a disc, film or sheet (e.g., ribbon-like) or the like.Flexibility may be a consideration so as to facilitate placement of thedrug depot. In various embodiments, the drug depot can be differentsizes, for example, the drug depot may be a length of from about 0.5 mmto 5 mm and have a diameter of from about 0.01 to about 4 mm. In variousembodiments, as the diameter decreases, the surface area that comes incontact with the bodily fluid of the depot increases and thereforerelease of the drug from the depot increases. In various embodiments,the drug depot may have a layer thickness of from about 0.005 to 1.0 mm,such as, for example, from 0.05 to 0.75 mm.

Radiographic markers can be included on the drug depot to permit theuser to position the depot accurately into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium phosphate, bismuth, iodine, tantalum, tungsten, and/ormetal beads or particles. In various embodiments, the radiographicmarker could be a spherical shape or a ring around the depot.

FIG. 1 illustrates a number of common locations within a patient thatmay be sites at which pain can occur and at which the clonidine may beadministered. It will be recognized that the locations illustrated inFIG. 1 are merely exemplary of the many different locations at whichpain can occur. For example, pain relief may be required at a patient'sknees 21, hips 22, fingers 23, thumbs 24, neck 25, and spine 26.

Gel

In various embodiments, the clonidine and GABA compound is administeredin a gel. The gel may have a pre-dosed viscosity in the range of about 1to about 2000 centipoise (cps), 1 to about 200 cps, or 1 to about 100cps. After the gel is administered to the target site, the viscosity ofthe gel will increase and the gel will have a modulus of elasticity(Young's modulus) in the range of about 1×−10² to about 6×10⁵ dynes/cm²,or 2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In one embodiment, a depot comprises an adherent gel comprisingclonidine that is evenly distributed throughout the gel. The gel may beof any suitable type, as previously indicated, and should besufficiently viscous so as to prevent the gel from migrating from thetargeted delivery site once deployed; the gel should, in effect, “stick”or adhere to the targeted tissue site. The gel may, for example,solidify upon contact with the targeted tissue or after deployment froma targeted delivery system. The targeted delivery system may be, forexample, a syringe, a catheter, needle or cannula or any other suitabledevice. The targeted delivery system may inject the gel into or on thetargeted tissue site. The therapeutic agent may be mixed into the gelprior to the gel being deployed at the targeted tissue site. In variousembodiments, the gel may be part of a two-component delivery system andwhen the two components are mixed, a chemical process is activated toform the gel and cause it to stick or to adhere to the target tissue.

In various embodiments, a gel is provided that hardens or stiffens afterdelivery. Typically, hardening gel formulations may have a pre-dosedmodulus of elasticity in the range of about 1×−10² to about 3×10⁵dynes/cm², or 2×10⁴ to about 2×10⁵ dynes/cm², or 5×10⁴ to about 1×10⁵dynes/cm². The post-dosed hardening gels (after delivery) may have arubbery consistency and have a modulus of elasticity in the range ofabout 1×−10² to about 2×10⁶ dynes/cm², or 1×10⁵ to about 7×10⁵dynes/cm², or 2×10⁵ to about 5×10⁵ dynes/cm².

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances. In some embodiments, the polymer comprises 20 wt. % to90 wt. % of the formulation.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The choice of method to vary molecularweight is typically determined by the composition of the gel (e.g.,polymer, versus non-polymer). For example in various embodiments, whenthe gel comprises one or more polymers, the degree of polymerization canbe controlled by varying the amount of polymer initiators (e.g. benzoylperoxide), organic solvents or activator (e.g. DMPT), crosslinkingagents, polymerization agent, incorporation of chain transfer or chaincapping agents and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel that includes a high molecular weight polymer tends tocoagulate or solidify more quickly than a polymeric composition thatincludes a low-molecular weight polymer. Polymeric gel formulations thatinclude high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel that includes low-molecularweight polymers. In various embodiments, the molecular weight of thepolymer can be a wide range of values. The average molecular weight ofthe polymer can be from about 1000 to about 10,000,000 Da; or about1,000 to about 1,000,000 Da; or about 5,000 Da to about 500,000 Da; orabout 10,000 Da to about 100,000 Da; or about 20,000 Da to 50,000 Da.

When the gel is designed to be a flowable gel, it can vary from lowviscosity, similar to that of water, to high viscosity, similar to thatof a paste, depending on the molecular weight and concentration of thepolymer used in the gel. The viscosity of the gel can be varied suchthat the polymeric composition can be applied to a patient's tissues byany convenient technique, for example, by brushing, dripping, injecting,or painting. Different viscosities of the gel will depend on thetechnique used to apply the composition.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and may have a longerdegradation time). Typically, when the polymers have similar componentsbut different MWs, a gel with a high molecular weight provides astronger matrix and the matrix takes more time to degrade. In contrast,a gel with a low molecular weight degrades more quickly and provides asofter matrix. In various embodiments, the gel has a molecular weight,as shown by the inherent viscosity, from about 0.10 dL/g to about 1.2dL/g or from about 0.10 dL/g to about 0.40 dL/g. Other IV ranges includebut are not limited to about 0.05 to about 0.15 dL/g, about 0.10 toabout 0.20 dL/g, about 0.15 to about 0.25 dL/g, about 0.20 to about 0.30dL/g, about 0.25 to about 0.35 dL/g, about 0.30 to about 0.35 dL/g,about 0.35 to about 0.45 dL/g, about 0.40 to about 0.45 dL/g, about 0.45to about 0.50 dL/g, about 0.50 to about 0.70 dL/g, about 0.60 to about0.80 dL/g, about 0.70 to about 0.90 dL/g, about 0.80 to about 1.00 dL/g,about 0.90 to about 1.10 dL/g, about 1.0 to about 1.2 dL/g, about 1.1 toabout 1.3 dL/g, about 1.2 to about 1.4 dL/g, about 1.3 to about 1.5dL/g, about 1.4 to about 1.6 dL/g, about 1.5 to about 1.7 dL/g, about1.6 to about 1.8 dL/g, about 1.7 to about 1.9 dL/g, and about 1.8 toabout 2.1 dL/g.

In some embodiments, when the polymer materials have differentchemistries (e.g., high MW DLG 5050 and low MW DL), the high MW polymermay degrade faster than the low MW polymer.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, or from about 15 cps to about 75 cps at room temperature. Thegel may optionally have a viscosity enhancing agent such as, forexample, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl methylcellulose, carboxymethylcellulose and salts thereof,Carbopol, poly-(hydroxyethylmethacrylate),poly-(methoxyethylmethacrylate), poly(methoxyethoxyethyl methacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400,PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG3350, PEG 4500, PEG 8000 or combinations thereof.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. A desirable property for the hydrogel to have is the ability torespond rapidly to mechanical stresses, particularly shears and loads,in the human body.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid andpoly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol(e.g., PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with clonidine. In one embodiment, themicrospheres provide for a sustained release of the clonidine. In yetanother embodiment, the gel, which is biodegradable, prevents themicrospheres from releasing the clonidine; the microspheres thus do notrelease the clonidine until they have been released from the gel. Forexample, a gel may be deployed around a target tissue site (e.g., anerve root). Dispersed within the gel may be a plurality of microspheresthat encapsulate the desired therapeutic agent. Certain of thesemicrospheres degrade once released from the gel, thus releasing theclonidine and GABA compound.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse theclonidine and GABA compound. In some situations, this may be desirable;in others, it may be more desirable to keep the clonidine and GABAcompound tightly constrained to a well-defined target site. The presentinvention also contemplates the use of adherent gels to so constraindispersal of the therapeutic agent. These gels may be deployed, forexample, in a disc space, in a spinal canal, or in surrounding tissue.

Drug Delivery

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a “cannula” or “needle” thatcan be a part of a drug delivery device e.g., a syringe, a gun drugdelivery device, or any medical device suitable for the application of adrug to a targeted organ or anatomic region. The cannula or needle ofthe drug depot device is designed to cause minimal physical andpsychological trauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space, for example, alongan inflammed nerve root and the drug depot implanted at this site fortreating the condition. Typically, the transforaminal approach involvesapproaching the intervertebral space through the intervertebralforamina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 15 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes, but is not limited to, from about0.05 to about 1.655 (mm). The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 22 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the site beneath the skin, so that the user may accurately positionthe depot at or near the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample, X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include, but are not limited to, barium, bismuth, tantalum,tungsten, iodine, calcium, and/or metal beads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, X-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot, and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requireindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot and/or one or morecomponents of the device, including, but not limited to, gassterilization, such as, for example, with ethylene oxide or steamsterilization.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot and/or medical device combined togetherto be used to implant the drug depot. The kit may include the drug depotdevice in a first compartment. The second compartment may include acanister holding the drug depot and any other instruments needed for thelocalized drug delivery. A third compartment may include gloves, drapes,wound dressings and other procedural supplies for maintaining sterilityof the implanting process, as well as an instruction booklet. A fourthcompartment may include additional cannulas and/or needles. A fifthcompartment may include an agent for radiographic imaging. Each tool maybe separately packaged in a plastic pouch that is radiation sterilized.A cover of the kit may include illustrations of the implanting procedureand a clear plastic cover may be placed over the compartments tomaintain sterility. In some embodiments, a kit is provided withinstruction to use an injectable drug from another kit.

In various embodiments, a method for delivering a therapeutic agent intoa site of a patient is provided, the method comprising inserting acannula at or near a target tissue site and implanting the drug depot atthe target site beneath the skin of the patient and brushing, dripping,injecting, or painting the gel in the target site to hold or have thedrug depot adhere to the target site. In this way unwanted migration ofthe drug depot away from the target site is reduced or eliminated.

In various embodiments, to administer the gel having the drug depotdispersed therein to the desired site, first the cannula or needle canbe inserted through the skin and soft tissue down to the target tissuesite and the gel administered at or near the target site. In thoseembodiments where the drug depot is separate from the gel, first thecannula or needle can be inserted through the skin and soft tissue downto the site of injection and one or more base layer(s) of gel can beadministered to the target site. Following administration of the one ormore base layer(s), the drug depot can be implanted on or in the baselayer(s) so that the gel can hold the depot in place or reducemigration. If required, a subsequent layer or layers of gel can beapplied on the drug depot to surround the depot and further hold it inplace. Alternatively, the drug depot may be implanted first and then thegel placed around the drug depot to hold it in place. By using the gel,accurate and precise implantation of a drug depot can be accomplishedwith minimal physical and psychological trauma to the patient. The gelalso avoids the need to suture the drug depot to the target sitereducing physical and psychological trauma to the patient.

In various embodiments, when the target site comprises a spinal region,a portion of fluid (e.g., spinal fluid, etc.) can be withdrawn from thetarget site through the cannula or needle first and then the depotadministered (e.g., placed, dripped, injected, or implanted, etc.). Thetarget site will re-hydrate (e.g., replenishment of fluid) and thisaqueous environment will cause the drug to be released from the depot.

One exemplary embodiment where the depot is suitable for use in treatingspasticity (e.g., neuropathic pain management) and/or to treatconditions (e.g., sciatica) is illustrated in FIG. 2. Schematicallyshown in FIG. 2 is a dorsal view of the spine 30 and sites where thedrug depot may be inserted using a cannula or needle beneath the skin 34to a spinal site 32 (e.g., spinal disc space, spinal canal, soft tissuesurrounding the spine, nerve root, etc.) and one or more drug depots 28and 32 are delivered to various sites along the spine. In this way, whenseveral drug depots are to be implanted, they are implanted in a mannerthat optimizes location, accurate spacing, and drug distribution.

Although the spinal site is shown, as described above, the drug depotcan be delivered to any site beneath the skin, including, but notlimited to, at least one muscle, ligament, tendon, cartilage, spinaldisc, spinal foraminal space, near the spinal nerve root, or spinalcanal.

In some embodiments, it is preferable to co-administer clonidine andGABA compound with an antagonist to counteract undesirable effects, forexample the blood pressure decrease that can be caused by clonidine.Exemplary antagonists include but are not limited to phentolamine,yohimbine, tolazoline and piperoxane. Additionally, compounds such as5-fluorodeoxyuridine (FUDR) and 3,4 dehydroprolene may also be included.These compounds may prevent or reduce glial and fibroblastic scarformation associated with some types of surgeries.

The clonidine ad GABA compound formulation of the present applicationmay be used as medicaments in the form of pharmaceutical preparations.The preparations may be formed in an administration with a suitablepharmaceutical carrier that may be solid or liquid and organic orinorganic, and placed in the appropriate form for parenteral or otheradministration as desired. As persons of ordinary skill are aware, knowncarriers include but are not limited to water, saline solution, gelatin,lactose, starches, stearic acid, magnesium stearate, sicaryl alcohol,talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol,polyalkylene glycols and other known carriers for medicaments.

Parenteral administration may additionally include, for example, aninfusion pump that administers a pharmaceutical composition (e.g.,analgesic and anti-inflammatory combination) through a catheter near thespine or one or more inflamed joints, an implantable mini-pump that canbe inserted at or near the target site, an implantable controlledrelease device or sustained release delivery system that can release acertain amount of the statin per hour or in intermittent bolus doses.One example of a suitable pump for use is the SynchroMed® (Medtronic,Minneapolis, Minn.) pump. This pump has three sealed chambers. Onecontains an electronic module and battery. The second contains aperistaltic pump and drug reservoir. The third contains an inert gasthat provides the pressure needed to force the pharmaceuticalcomposition into the peristaltic pump. To fill the pump, thepharmaceutical composition is injected through the reservoir fill portto the expandable reservoir. The inert gas creates pressure on thereservoir, and the pressure forces the pharmaceutical compositionthrough a filter and into the pump chamber. The pharmaceuticalcomposition is then pumped out of the device from the pump chamber andinto the catheter, which will direct it for deposit at the target site.The rate of delivery of pharmaceutical composition is controlled by amicroprocessor. This allows the pump to be used to deliver similar ordifferent amounts of pharmaceutical composition continuously,continually, at specific times, or at set intervals between deliveries.

Another embodiment is directed to a method for treating a mammalsuffering from pain, said method comprising administering atherapeutically effective amount of clonidine and GABA compound at atarget site beneath the skin. The clonidine and GABA compound (orpharmaceutically acceptable salt) may for example be administeredlocally to the target tissue site as a drug depot.

In some embodiments, the clonidine and GABA compound is encapsulated ina plurality of depots comprising microparticles, microspheres,microcapsules, and/or microfibers.

In some embodiments there is a method for making an implantable drugdepot. The method may comprise combining a biocompatible polymer and atherapeutically effective amount of clonidine and GABA compound or apharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.

In some embodiments, the clonidine and GABA compound is suitable forparenteral administration. The term “parenteral” as used herein refersto modes of administration that bypass the gastrointestinal tract, andinclude for example, intravenous, intramuscular, continuous orintermittent infusion, intraperitoneal, intrasternal, subcutaneous,intra-operatively, intrathecally, intradiscally, peridiscally,epidurally, perispinally, intraarticular injection or combinationsthereof. In some embodiments, the injection is intrathecal, which refersto an injection into the spinal canal (intrathecal space surrounding thespinal cord). An injection may also be into a muscle or other tissue.

In various embodiments, the drug depot comprising the clonidine and GABAcompound can be made by combining a biocompatible polymer and atherapeutically effective amount of clonidine or pharmaceuticallyacceptable salt thereof and forming the implantable drug depot from thecombination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: clonidine and other therapeuticagent(s) and other optional additives such as radiographic agent(s),etc. in dissolved or dispersed form. This results in a polymeric matrixregion containing these species after solvent removal. In otherembodiments, a solution containing solvent with dissolved or dispersedtherapeutic agent is applied to a pre-existing polymeric region, whichcan be formed using a variety of techniques including solutionprocessing and thermoplastic processing techniques, whereupon thetherapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: clonidine andGABA compound, optional additional therapeutic agent(s), radiographicagent(s), and so forth. The resulting mixture is then shaped into animplantable drug depot. The mixing and shaping operations may beperformed using any of the conventional devices known in the art forsuch purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, clonidine may undergo substantial degradationunder ordinary thermoplastic processing conditions. Hence, processing ispreferably performed under modified conditions, which prevent thesubstantial degradation of the therapeutic agent(s). Although it isunderstood that some degradation may be unavoidable during thermoplasticprocessing, degradation is generally limited to 10% or less. Among theprocessing conditions that may be controlled during processing to avoidsubstantial degradation of the therapeutic agent(s) are temperature,applied shear rate, applied shear stress, residence time of the mixturecontaining the therapeutic agent, and the technique by which thepolymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the clonidine and GABA compound containing drugdepot. Conversely, in another embodiment, the biocompatible polymer canbe precompounded with the therapeutic agent under conditions of reducedtemperature and mechanical shear. This precompounded material is thenmixed with, for example, a radio-opacifying agent, also under conditionsof reduced temperature and mechanical shear, and the resulting mixtureis shaped into the drug depot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear (e.g., clonidine), invarious embodiments, the PGLA or PLA can be premixed with theradio-opacifying agent at temperatures of about, for example, 150° C. to170° C. The therapeutic agent is then combined with the premixedcomposition and subjected to further thermoplastic processing atconditions of temperature and mechanical shear that are substantiallylower than is typical for PGLA or PLA compositions. For example, whereextruders are used, barrel temperature, volumetric output are typicallycontrolled to limit the shear and therefore to prevent substantialdegradation of the therapeutic agent(s). For instance, the therapeuticagent and premixed composition can be mixed/compounded using a twinscrew extruder at substantially lower temperatures (e.g., 100-105° C.),and using substantially reduced volumetric output (e.g., less than 30%of full capacity, which generally corresponds to a volumetric output ofless than 200 cc/min). It is noted that this processing temperature iswell below the melting points of clonidine and GABA compound becauseprocessing at or above these temperatures will result in substantialtherapeutic agent degradation. It is further noted that in certainembodiments, the processing temperature will be below the melting pointof all bioactive compounds within the composition, including thetherapeutic agent. After compounding, the resulting depot is shaped intothe desired form, also under conditions of reduced temperature andshear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet) is cooled. Examples of cooling processesinclude air cooling and/or immersion in a cooling bath. In someembodiments, a water bath is used to cool the extruded depot. However,where a water-soluble therapeutic agent such as clonidine and GABAcompound are used, the immersion time should be held to a minimum toavoid unnecessary loss of therapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, clonidine is used and mixed orsprayed with the PLGA or PEG550 polymer, and the resulting depot may beformed by extrusion and dried.

In various embodiments, there is a pharmaceutical formulationcomprising: clonidine and a GABA compound, wherein the clonidinecomprises from about 0.1 wt. % to about 30 wt. % of the formulation, andat least one biodegradable polymer. In some embodiments, the clonidinecomprises from about 3 wt. % to about 20 wt. %, about 3 wt. % to about18 wt. %, about 5 wt. % to about 15 wt. % or about 7.5 wt. % to about12.5 wt. % of the formulation. By way of example, when using a 5%-15%clonidine composition, the mole ratio of clonidine to polymer would befrom approximately 16-53 when using an approximately 80 kDalton polymerthat has a 267 grams/mole ratio. By way of another example, when using a5%-15% clonidine base in the composition, the mole ratio of clonidinebase to polymer would be from approximately 18-61 with a mole mass of230 g/mol.

In some embodiments, the GABA compound can be in the formulation with orwithout clonidine. In some embodiments, the GABA compound is in theformulation at about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% byweight based on the total weight of the formulation.

In some embodiments, the drug depot comprises at least one biodegradablematerial in a wt % of about 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%,92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%,78%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 65%, 60%, 55%, 50%, 45%, 35%,25%, 20%, 15%, 10%, or 5% based on the total weight of the depot and theremainder is active and/or inactive pharmaceutical ingredients.

In some embodiments, the at least one biodegradable polymer comprisespoly(lactic-co-glycolide) (PLGA) or poly(orthoester) (POE) or acombination thereof. The poly(lactic-co-glycolide) may comprise amixture of polyglycolide (PGA) and polylactide and in some embodiments,in the mixture, there is more polylactide than polyglycolide. In variousembodiments there is 100% polylactide and 0% polyglycolide; 95%polylactide and 5% polyglycolide; 90% polylactide and 10% polyglycolide;85% polylactide and 15% polyglycolide; 80% polylactide and 20%polyglycolide; 75% polylactide and 25% polyglycolide; 70% polylactideand 30% polyglycolide; 65% polylactide and 35% polyglycolide; 60%polylactide and 40% polyglycolide; 55% polylactide and 45%polyglycolide; 50% polylactide and 50% polyglycolide; 45% polylactideand 55% polyglycolide; 40% polylactide and 60% polyglycolide; 35%polylactide and 65% polyglycolide; 30% polylactide and 70%polyglycolide; 25% polylactide and 75% polyglycolide; 20% polylactideand 80% polyglycolide; 15% polylactide and 85% polyglycolide; 10%polylactide and 90% polyglycolide; 5% polylactide and 95% polyglycolide;and 0% polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In various embodiments, the drug particle size (e.g., clonidine and GABAcompound) is from about 5 to 30 micrometers, however, in variousembodiments ranges from about 1 micron to 250 microns may be used. Insome embodiments, the biodegradable polymer comprises at least 50 wt. %,at least 60 wt. %, at least 70 wt. %, at least 80 wt. % of theformulation, at least 85 wt. % of the formulation, at least 90 wt. % ofthe formulation, at least 95 wt. % of the formulation or at least 97 wt.% of the formulation. In some embodiments, the at least onebiodegradable polymer and the clonidine are the only components of thepharmaceutical formulation.

In some embodiments, at least 75% of the particles have a size fromabout 10 micrometer to about 200 micrometers. In some embodiments, atleast 85% of the particles have a size from about 10 micrometer to about200 micrometers. In some embodiments, at least 95% of the particles havea size from about 10 micrometer to about 200 micrometers. In someembodiments, all of the particles have a size from about 10 micrometerto about 200 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 20 micrometer to about 180 micrometers. In some embodiments, atleast 85% of the particles have a size from about 20 micrometers toabout 180 micrometers. In some embodiments, at least 95% of theparticles have a size from about 20 micrometer to about 180 micrometers.In some embodiments, all of the particles have a size from about 20micrometer to about 180 micrometers. In some embodiments, at least 80%of the particles have a size from 5 microns to about 100 microns on avolume basis.

In some embodiments, there is a pharmaceutical formulation comprising:clonidine, wherein the clonidine is in the form of a hydrochloride salt,and comprises from about 0.1 wt. % to about 30 wt. % of the formulation,and at least one biodegradable polymer, wherein the at least onebiodegradable polymer comprises poly(lactide-co-glycolide) (orpoly(lactic-co-glycolic acid)) or poly(orthoester) or a combinationthereof, and said at least one biodegradable polymer comprises at least70 wt. % of said formulation.

In some embodiments, the drug depot comprises about 95 wt %poly(D,L-lactide) and 5 wt % clonidine HCl where the polymer has anester end group and 70,000 Da MW and an IV 0.45-0.55 dL/g and has aburst release of under 10% of the amount of drug in the depot within 24hours (e.g., 5-10 wt %) or 2-40 mcg in 24 hours. This formulation has50% of total cumulative dose remaining for at least 60 days. About 80%of the particles in this depot including the clonidine are from about 5to about 150 microns or 5-100 microns. The depot releases about 0.5mcg/day up to about 5 mcg/day of clonidine in 24 hours and thencontinues release for 70 days.

In some embodiments, the drug depot comprises about 92 wt %poly(D,L-lactide) and 8 wt % clonidine HCl where the polymer has anester end group and the polymer comprises 70,000 Da MW and an IV ofabout 0.45-0.55 dL/g and has a burst release of under 10% of the amountof drug in the depot within 24 hours (e.g., 5-10%) or 5-6 mcg in 24hours and then 1 to 20 mcg/day with a constant release for about 50days, and then about 0.1 mcg to about 10 mcg/day for 70 days. Thisformulation has 50% of total cumulative dose remaining for at least30-42 days and less than 80% cumulative drug release by 70 days. About80% of the particles in this depot including the clonidine are fromabout 5 to about 150 microns or 5-100 microns.

In some embodiments, the drug depot comprises about 85 wt %poly(D,L-lactide) and 15 wt % clonidine HCl where the polymer has anester end group and the polymer comprises 70,000 Da MW and an IV ofabout 0.45-0.55 dL/g and has a burst release of under 10% of the amountof drug in the depot within 24 hours (e.g., 5-10%) or 20-150 mcg in 24hours and then 5 to 80 mcg/day with a constant release for about 30days, and then about 0.1 mcg to about 5 mcg/day for 70 days. Thisformulation has about 80% of total cumulative dose released within 35days and 20% over several months. About 80% of the particles in thisdepot including the clonidine are from about 5 to about 150 microns or5-100 microns.

In some embodiments, there is a pharmaceutical formulation comprisingclonidine, wherein the clonidine is in a mixture of clonidinehydrochloride and clonidine base and the mixture comprises from about0.1 wt. % to about 30 wt. % of the formulation and a polymer comprisesat least 70% of the formulation. In some embodiments, the polymer inthis formulation is polyorthoester.

In some embodiments, the formulation comprises a drug depot thatcomprises abiodegradable polyorthoester. The mechanism of thedegradation process of the polyorthoester can be hydrolytical orenzymatical in nature, or both. In various embodiments, the degradationcan occur either at the surface of the drug depot (heterogeneous orsurface erosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion). Polyorthoester can be obtained from A.P.Pharma, Inc. (Redwood City, Calif.) or through the reaction of abis(ketene acetal) such as3,9-diethylidene-2,4,8,10-tetraoxospiro[5,5]undecane (DETOSU) withsuitable combinations of diol(s) and/or polyol(s) such as1,4-trans-cyclohexanedimethanol and 1,6-hexanediol or by any otherchemical reaction that produces a polymer comprising orthoestermoieties.

In some embodiments, there are methods for treating acute pain. Thesemethods comprise: administering a pharmaceutical composition to anorganism, wherein said pharmaceutical composition (e.g., clonidine andGABA compound) comprises from about 0.1 wt. % to about 30 wt. % of theformulation, and at least one biodegradable polymer. In someembodiments, the loading is from about 1 wt % to about 25 wt %, or about5 wt. % to about 10 wt. %. In some embodiments, the loading is fromabout 10 wt. % to about 20 wt. %.

In some embodiment there is a higher loading of clonidine and GABAcompound, e.g., at least 20 wt. %, at least 30 wt. %, at least 40 wt. %,at least 50 wt. %, at least 60 wt. %, at least 70 wt. %, at least 80 wt.%, or at least 90 wt. %.

A strategy of triangulation may be effective when administering thesepharmaceutical formulations. Thus, a plurality (at least two, at leastthree, at least four, at least five, at least six, at least seven, etc.)drug depots comprising the pharmaceutical formulations may be placedaround the target tissue site (also known as the pain generator or paingeneration site) such that the target tissue site falls within a regionthat is either between the formulations when there are two, or within anarea whose perimeter is defined by a set of plurality of formulations.

In some embodiments, the formulations are slightly rigid with varyinglength, widths, diameters, etc. For example, certain formulations mayhave a diameter of 0.50 mm and a length of 4 mm. It should be noted thatparticle size may be altered by techniques such as mort and pestle,jet-drying or jet milling.

In some embodiments, clonidine is released at a rate of 2-3 μg per dayfor a period of at least three days. In some embodiments, this releaserate continues for, at least ten days, at least fifteen days, at leasttwenty-five days, at least fifty days, at least ninety days, at leastone hundred days, at least one-hundred and thirty-five days, at leastone-hundred and fifty days, or at least one hundred and eighty days. Forsome embodiments, 300-425 micrograms of clonidine as formulated with abiopolymer are implanted into a person at or near a target tissue site.If clonidine is implanted at multiple sites that triangulate the targetsite then in some embodiments, the total amount of clonidine at eachsite is a fraction of the total 300-425 micrograms. For example, one mayimplant a single dose of 324 micrograms at one site, or two separatedoses of 162 micrograms at two sites, or three separate dose of 108micrograms at three sites that triangulate the tissue site. It isimportant to limit the total dosage to an amount less than that whichwould be harmful to the organism. However, in some embodiments, althoughwhen there are a plurality of sites each site may contain less than thetotal dose that might have been administered in a single application, itis important to remember that each site will independent have a releaseprofile, and the biopolymers' concentration and substance should beadjusted accordingly to ensure that the sustain release occurs oversufficient time.

The dosage may be from approximately 0.0005 to approximately 960 μg/day.Additional dosages of clonidine include from approximately 0.0005 toapproximately 900 μg/day; approximately 0.0005 to approximately 500μg/day; approximately 0.0005 to approximately 250 μg/day; approximately0.0005 to approximately 100 μg/day; approximately 0.0005 toapproximately 75 μg/day; approximately 0.001 to approximately 70 μg/day;approximately 0.001 to approximately 65 μg/day; approximately 0.001 toapproximately 60 μg/day; approximately 0.001 to approximately 55 μg/day;approximately 0.001 to approximately 50 μg/day; approximately 0.001 toapproximately 45 μg/day; approximately 0.001 to approximately 40 μg/day;approximately 0.001 to approximately 35 μg/day; approximately 0.0025 toapproximately 30 μg/day; approximately 0.0025 to approximately 25μg/day; approximately 0.0025 to approximately 20 μg/day; approximately0.0025 to approximately 15 μg/day; approximately 0.0025 to approximately10 μg/day; approximately 0.0025 to approximately 5 μg/day; andapproximately 0.0025 to approximately 2.5 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 15μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to approximately 10 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 5μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to 2.5 μg/day. In some embodiments, the amount ofclonidine is between 40 and 600 μg/day. In some embodiments, the amountof clonidine is between 200 and 400 μg/day.

In some embodiments, the therapeutically effective dosage amount (e.g.,clonidine dose and GABA compound) and the release rate profile aresufficient to reduce inflammation and/or pain for a period of at leastone day, for example, 1-90 days, 1-10 days, 1-3 days, 3-7 days, 3-12days; 3-14 days, 7-10 days, 7-14 days, 7-21 days, 7-30 days, 7-50 days,7-90 days, 7-140 days, 14-140 days, 3 days to 135 days, 3 days to 180days, or 3 days to 6 months or 1 year or longer.

In some embodiments the clonidine and GABA compound in the depot isdesigned for a bolus dose or burst dose within 1, 2, or 3 days afterimplantation to provide an immediate release of the clonidine and GABAcompound for treatment of pain and/or inflammation.

In some embodiments, the clonidine and GABA compound depot isadministered parenterally, e.g., by injection. In some embodiments, theinjection is intrathecal, which refers to an injection into the spinalcanal (intrathecal space surrounding the spinal cord). An injection mayalso be into a muscle or other tissue. In other embodiments, theclonidine depot is administered by placement into an open patient cavityduring surgery.

In some embodiments, the drug depot (i) comprises one or more immediaterelease layer(s) that is capable of releasing about 5% to about 20% ofthe clonidine and GABA compound or pharmaceutically acceptable saltsthereof relative to a total amount of the clonidine and GABA compound orpharmaceutically acceptable salt thereof loaded in the drug depot over afirst period of up to 48 hours and (ii) one or more sustain releaselayer(s) that is capable of releasing about 21% to about 99% of theclonidine and GABA compound or pharmaceutically acceptable salt thereofrelative to a total amount of the clonidine and GABA compound orpharmaceutically acceptable salt thereof loaded in the drug depot over asubsequent period of up to 3 days to 90 days, 150 days, 180 days, or 6months to 1 year.

In some embodiments, there is a drug depot comprising clonidine orclonidine hydrochloride and a GABA compound and a polymer, wherein thepolymer is one more of various embodiments, the drug depot comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone or a combination thereof.

In one exemplary dosing regimen, a rat may be provided with sufficientclonidine in a biodegradable polymer to provide sustain release of 0.240μg/day for 135 days. The total amount of clonidine that is administeredover this time period would be approximately 32.4 μg. In anotherexemplary dosing regimen, a human is provided with sufficient clonidinein a biodegradable polymer to provide sustain release of 2.4 μg/day for135 days. The total amount of clonidine that is administered over thistime period would be approximately 324 μg. In another exemplary dosingregimen, a human is provided with sufficient clonidine in abiodegradable polymer to provide sustain release of 0.5 μg/day to about5 μg/day in 24 hours, continuing for 70 days.

When using a plurality of pellets, the pellet number is based on theamount of drug loading into a pellet of appropriate size (i.e., 0.5 mmdiameter×4 mm length) and how much drug is needed (e.g., approximately325 μg clonidine (3 pellets)). In some embodiments, 3 to 6 pellets areused. In some embodiments there is a polymer that releases a bolusamount of compound over the first few (−5) days before it settles downand releases 2.5 mg/day for 135 days. An exemplary formulation is 5% wt.clonidine, 100 DL 5E (Surmodics Pharmaceuticals, Birmingham, Ala.).

In some embodiments, the polymer depots of present invention enable oneto provide efficacy of the active ingredient that is equivalent tosubcutaneous injections that deliver more than 2.5 times as much drug.

In some embodiments, the drug depot comprises a polymer having 60 mol. %poly L-lactide and 40 mol. % caprolactone, where thepoly(L-lactide-co-caprolactone) has a MW of 30,000 to 35,000 Da and anIV of about 0.5-0.6 dL/g and has a burst release of under 25% of theamount of drug in the depot within 24 hours (e.g., 5-15% within 4hours). The drug depot comprises clonidine in an amount of 3-8 wt. %.The depot releases 400 mcg to about 1000 mcg for 7 days, which is about40 mcg/day. This depot does not contain excipients. The clonidine has aparticle size of 5 microns or less and a 90% VD less than 20 microns.The degradation time in the body is not more than 3 months and the drugdepot releases all of the clonidine within 2 weeks.

In some embodiments, the drug depot comprises a polymer having 10 mol. %poly D-L-lactide and 90 mol. % caprolactone, where thepoly(D,L-lactide-co-caprolactone) has a MW of 50,000 to 125,000 Da andan IV of about 0.6 dL/g and has a burst release of under 25% of theamount of drug in the depot within 24 hours (e.g., 5-15% within 4hours). The drug depot comprises clonidine in an amount of 3-10 wt. %.The depot releases 400 mcg to about 1000 mcg for 7 days, which is about40 mcg/day. This depot contains from about 1% to about 5% by weight ofmannitol or trehalose as a pore forming agent or plasticizer. Theclonidine has a particle size of 5 microns or less and a 90% VD lessthan 20 microns. The degradation time in the body is not more than 3months and the drug depot releases all of the clonidine within 2 weeks.As you drop the drug load the drug released from the depot was faster.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

Examples

These examples show that gabapentin is effective in reducing two typesof pain associated with sciatic nerve constriction in the rat.

Rats were treated with a subcutaneous human equivalent dose of 885 mcgof gabapentin 1 hour prior to testing.

Eight Sprague Dawley rats were given a chronic constriction injury (CCI)of the sciatic nerve. The CCI was induced as described by Bennett andXie (1988). Animals were anesthetized with pentobarbital (60 mg/kg). Theright common sciatic nerve was exposed by blunt dissection between thefemoral biceps and quadriceps muscle and freed from adherent tissue.Four loose ligatures were placed 1 mm apart using 4-0 chromic gutabsorbable sutures. Four animals received a subcutaneous injection ofgabapentin (90 mg/kg) 1 hour prior to each post-CCI pain assessment (BP)and four animals received vehicle (PBS) injections. Thermal hyperalgesiapaw withdrawal latency response of the injured (rt) limb was measured 2days before the CCI and on days 7, 14, and 21 post-CCI surgery. This isconsidered a model of neuropathic pain. FIG. 3 is a bar graphillustration showing that Von Frey withdrawal threshold is increased bygabapentin in rats with an injury to the sciatic nerve.

Mechanical paw withdrawal (allodynia) thresholds of each animal weremeasured the day before the CCI and on days 8, 15, and 22. FIG. 4 is abar graph illustration showing that thermal withdrawal latency isincreased by gabapentin in rats with an injury to the sciatic nerve.This is considered a model of tactile somatic pain. Von Frey threshold,expressed as a percent of baseline, was significantly higher in the GPgroup (2-factor ANOVA, p<0.001).

Thermal withdrawal latency, expressed as a percent of baseline, wassignificantly higher in the GP group (2-factor ANOVA, p<0.0001). Theseresults show that gabapentin is effective in reducing two types of painassociated with sciatic nerve constriction in the rat.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

1. An implantable device for reducing or treating pain in a patient inneed of such treatment, the implantable device comprising clonidine anda gamma-aminobutyric acid (GABA) compound in an amount from about 0.1wt. % to about 99 wt. % of the implantable device, and at least onebiodegradable polymer, wherein the implantable device is capable ofreleasing clonidine and the GABA compound over a period of at leastthree days.
 2. An implantable device according to claim 1, wherein theimplantable device is a drug depot comprising clonidine and the GABAcompound comprises from about 1 wt. % to about 40 wt. % of the drugdepot.
 3. An implantable drug depot according to claim 2, wherein saidat least one biodegradable polymer comprises at least 70 wt. % of thedrug depot.
 4. An implantable drug depot according to claim 2, whereinsaid at least one biodegradable polymer comprises at least 90 wt. % ofthe drug depot.
 5. An implantable drug depot according to claim 2,wherein the at least one biodegradable polymer comprises one or more ofpoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,L-lactide-co-ε-caprolactone, D,L-lactide-co-glycolide-co-ε-caprolactoneor a combination thereof.
 6. An implantable drug depot according toclaim 5, wherein (i) the at least one biodegradable polymer comprisespolylactide or (ii) the at least one biodegradable polymer comprisespoly(lactic-co-glycolide) and said poly(lactic-co-glycolide) comprises amixture of polyglycolide and polylactide.
 7. An implantable drug depotaccording to claim 6, wherein said mixture comprises more polylactidethan polyglycolide and the clonidine is an insoluble salt of clonidinecomprising a fatty acid salt.
 8. An implantable drug depot according toclaim 2, wherein said clonidine is in the form of clonidinehydrochloride or a mixture of clonidine base and a hydrochloride saltand the GABA compound comprises baclofen, vigabatrin, gabapentin,pregabalin, gamma-amino-phosphinic acid, or1-{[(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid or a combination thereof.
 9. An implantable drug depotaccording to claim 2, wherein the drug depot releases: (i) a bolus doseof the clonidine and the GABA compound at a site beneath the skin; and(ii) an effective amount of the clonidine and the GABA compound over aperiod of at least thirty days.
 10. An implantable drug depot accordingto claim 2, wherein the at least one biodegradable polymer comprisespoly(lactic-co-glycolide), poly(D,L-lactide), poly(orthoester) or acombination thereof, and said at least one biodegradable polymercomprises at least 70 wt. % of said drug depot.
 11. An implantable drugdepot for reducing or treating pain in a patient in need of suchtreatment, the implantable drug depot comprising clonidine hydrochloridein an amount of from about 0.1 wt. % to about 30 wt. % of the drug depotand baclofen, vigabatrin, gabapentin, pregabalin, gamma-amino-phosphinicacid, or1-{[(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid and at least one polymer, wherein the at least one polymercomprises one or more of poly(lactide-co-glycolide) (PLGA), polylactide(PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,L-lactide-co-ε-caprolactone, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone or a combination thereof 12.A method for treating acute pain, wherein said method comprisesimplanting a drug depot in an organism to reduce, prevent or treat pain,wherein said drug depot comprises clonidine in an amount from about 0.1wt. % to about 30 wt. % of the drug depot and baclofen, vigabatrin,gabapentin, pregabalin, gamma-amino-phosphinic acid or1-{[(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid, and at least one biodegradable polymer.
 13. A methodaccording to claim 12, wherein said clonidine comprises from about 5 wt.% to about 15 wt. % of the drug depot.
 14. A method according to claim12, wherein said biodegradable polymer comprises at least 70 wt. % ofthe drug depot.
 15. A method according to claim 12, wherein saidbiodegradable polymer comprises at least 90 wt. % of the drug depot. 16.A method according to claim 12, wherein (i) the at least onebiodegradable polymer comprises polylactide (PLA) or (ii) the at leastone biodegradable polymer comprises one or more ofpoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, polyorthoester (POE), D,L-lactide, L-lactide,D,L-lactide-co-caprolactone, L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-caprolactone or a combination thereof.
 17. Amethod according to claim 16, wherein the at least one biodegradablepolymer comprises poly(lactic-co-glycolide) and saidpoly(lactic-co-glycolide) comprises a mixture of polyglycolide andpolylactide.
 18. A method according to claim 17, wherein said mixturecomprises more polylactide than polyglycolide.
 19. A method according toclaim 12, wherein said clonidine is in the form of clonidinehydrochloride or a mixture of clonidine and a hydrochloride salt or aninsoluble fatty acid salt.
 20. A method according to claim 12, whereinsaid implanting comprises applying a said pharmaceutical composition ata plurality of sites that triangulate a pain generator.